A Multi-targeted Drug Candidate with Dual Anti-HIV and Anti-HSV Activity

• Published in: PLoS pathogens Vol. 9; no. 7; p. e1003456
• Main Authors: Balzarini, Jan, Andrei, Graciela, Balestra, Emanuela, Huskens, Dana, Vanpouille, Christophe, Introini, Andrea, Zicari, Sonia, Liekens, Sandra, Snoeck, Robert, Holý, Antonín, Perno, Carlo-Federico, Margolis, Leonid, Schols, Dominique
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.07.2013; Public Library of Science (PLoS)
• Subjects: Animals; Anti-HIV Agents - pharmacology; Anti-HIV Agents - therapeutic use; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - virology; Cells, Cultured; Chemokines; Cytokines; Deoxyribonucleic acid; DNA; Drug resistance in microorganisms; Female; Health aspects; Herpes Simplex - drug therapy; Herpes Simplex - immunology; Herpes Simplex - metabolism; Herpes Simplex - virology; Herpes simplex virus; Herpesvirus 1, Human - drug effects; Herpesvirus 1, Human - enzymology; Herpesvirus 1, Human - immunology; Herpesvirus 2, Human - drug effects; Herpesvirus 2, Human - enzymology; Herpesvirus 2, Human - immunology; HIV; HIV - drug effects; HIV - enzymology; HIV - immunology; HIV infection; Host-parasite relationships; Human immunodeficiency virus; Humans; Immunologic Factors - pharmacology; Immunologic Factors - therapeutic use; Infections; Leukocytes, Mononuclear - cytology; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - virology; Lymphoid Tissue - drug effects; Lymphoid Tissue - immunology; Lymphoid Tissue - metabolism; Lymphoid Tissue - virology; Medicine; Mice; Mice, Hairless; Mice, Nude; Nucleic Acid Synthesis Inhibitors - pharmacology; Nucleic Acid Synthesis Inhibitors - therapeutic use; Organophosphonates - pharmacology; Organophosphonates - therapeutic use; Physiological aspects; Prodrugs - pharmacology; Prodrugs - therapeutic use; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Reverse Transcriptase Inhibitors - pharmacology; Reverse Transcriptase Inhibitors - therapeutic use; Tissue Culture Techniques; Viruses; Czech Republic
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1003456

Human immunodeficiency virus (HIV) infection is often accompanied by infection with other pathogens, in particular herpes simplex virus type 2 (HSV-2). The resulting coinfection is involved in a vicious circle of mutual facilitations. Therefore, an important task is to develop a compound that is highly potent against both viruses to suppress their transmission and replication. Here, we report on the discovery of such a compound, designated PMEO-DAPym. We compared its properties with those of the structurally related and clinically used acyclic nucleoside phosphonates (ANPs) tenofovir and adefovir. We demonstrated the potent anti-HIV and -HSV activity of this drug in a diverse set of clinically relevant in vitro, ex vivo, and in vivo systems including (i) CD4⁺ T-lymphocyte (CEM) cell cultures, (ii) embryonic lung (HEL) cell cultures, (iii) organotypic epithelial raft cultures of primary human keratinocytes (PHKs), (iv) primary human monocyte/macrophage (M/M) cell cultures, (v) human ex vivo lymphoid tissue, and (vi) athymic nude mice. Upon conversion to its diphosphate metabolite, PMEO-DAPym markedly inhibits both HIV-1 reverse transcriptase (RT) and HSV DNA polymerase. However, in striking contrast to tenofovir and adefovir, it also acts as an efficient immunomodulator, inducing β-chemokines in PBMC cultures, in particular the CCR5 agonists MIP-1β, MIP-1α and RANTES but not the CXCR4 agonist SDF-1, without the need to be intracellularly metabolized. Such specific β-chemokine upregulation required new mRNA synthesis. The upregulation of β-chemokines was shown to be associated with a pronounced downmodulation of the HIV-1 coreceptor CCR5 which may result in prevention of HIV entry. PMEO-DAPym belongs conceptually to a new class of efficient multitargeted antivirals for concomitant dual-viral (HSV/HIV) infection therapy through inhibition of virus-specific pathways (i.e. the viral polymerases) and HIV transmission prevention through interference with host pathways (i.e. CCR5 receptor down regulation).